Benzimidazolinyl piperidines as CGRP ligands

ABSTRACT

The present invention relates to benzimidazolinylpiperidine derivatives useful as ligands for CGRP (Calcitonin Gene-Related Peptide) receptors, their use in therapy, pharmaceutical compositions comprising them and methods of treatment using them.

This application is a US National Phase application under 35 U.S.C. §371of PCT Application No. PCT/GB99/03154, filed on Sep. 22, 1999, whichclaims priority under 35 U.S.C. 119 to U.S. Provisional No. 60/102,492,filed on Sep. 30, 1998.

The present invention relates to benzimidazolinylpiperidine derivativesuseful as ligands for CGRP (Calcitonin Gene-Related Peptide) receptors,processes for their preparation, their use in therapy, pharmaceuticalcompositions comprising them and methods of treatment using them.

CGRP is a naturally occurring 37-amino acid peptide that is generated bytissue-specific alternate processing of calcitonin messenger RNA and iswidely distributed in the central and peripheral nervous system. CGRP islocalised predominantly in sensory afferent and central neurons andexhibits several biological actions, including vasodilation. CGRP isexpressed in α- and β-forms that vary by one and three amino acids inthe rat and human, respectively.

CGRPα and CGRPβ display similar biological properties. When releasedfrom the cell, CGRP initiates its biological responses by binding tospecific cell surface receptors that are predominantly coupled to theactivation of adenylyl cyclase. CGRP receptors have been identified andpharmacologically evaluated in several tissues and cells, includingthose of brain, cardiovascular, endothelial, and smooth muscle origin.

Based on pharmacological properties, these receptors are divided into atleast two subtypes, denoted CGRP₁ and CGRP₂. Human (h) CGRP-(8-37)α, afragment of CGRP that lacks seven N-terminal amino acid residues, is aselective antagonist of CGRP₁-Rs, whereas the linear analogue of CGRP,diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selectiveagonist of CGRP₂-Rs.

We have now surprisingly found a class of compounds which are ligands,and preferably antagonists for CGRP receptors. In particular, theypreferably bind selectively to human rather than rodent CGRP.

wherein:

R¹ is naphthyl or benzothienyl which is unsubstituted or substituted atup to three substitutable positions independently by C₁₋₆ alkyl,halogen, C₁₋₆ alkoxy, CF₃, OCF₃, NO₂, CN, methylenedioxy orethylenedioxy;

R² is hydrogen, C₁₋₈ alkyl, —(CH₂)_(t)-aryl wherein aryl is selectedfrom phenyl, biphenyl and naphthyl, —(CH₂)_(t)-heteroaryl wherinheteroaryl is selected from tetrazolyl, oxadiazolyl, thiadiazolyl,triazolyl and pyrazinyl, —(CH₂)_(q)C(O)OR⁶, —(CH₂)_(q)OR⁶,—(CH₂)_(q)OC(O)R⁶, —(CH₂)_(q)C(O)R⁶, —(CH₂)_(q)C(O)(CH₂)_(t)aryl,—(CH₂)_(q)N(R⁶)C(O)R⁶, —(CH₂)_(q)C(O)N(R⁶)₂, —(CH₂)_(q)N(R⁶)SO₂R⁶,—(CH₂)_(q)N(R₆)C(O)N(R⁶)₂, —(CH₂)_(q)OC(O)N(R⁶)₂,—(CH₂)_(q)N(R⁶)C(O)OR⁶, —(CH₂)_(q)N(R⁶)SO₂N(R⁶)₂ and —(CH₂)_(q)S(O)_(m)_(l R) ⁶;

R³ is NH₂;

R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, OCF₃ or CF₃;

R⁵ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, OCF₃ or CF₃;

R⁶ is hydrogen, C₁₋₈ alkyl or C₃₋₇ cycloalkyl, and when two R⁶ groupsare present and both represent C₁₋₈ alkyl they may optionally togetherwith the atom to which they are both attached form a C₃₋₈ ring;

Q is —(CH₂)_(x)—C(R⁷)(R^(7a))—(CH₂)_(y)— or —(CH₂)_(x)—V—(CH₂)_(y)—;

R⁷ and R^(7a) are independently chosen from hydrogen, CF₃, halogen, C₁₋₆alkyl and C₁₋₆ alkoxy;

V is a C₃₋₈ non-aromatic cyclic or bicyclic ring or an aromatic ringwhich is benzene or naphthalene, said ring being unsubstituted orsubstituted at up to three substitutable positions independently by C₁₋₆alkyl, C₁₋₆ alkoxy, halogen, OCF₃, CF₃, CN, NO₂, methylenedioxy orethylenedioxy;

m is 0, 1 or 2;

q is 0, 1, 2, 3 or 4;

t is 0, 1, 2 or 3;

x and y are independently 0, 1, 2, 3 or 4;

or a pharmaceutically acceptable salt thereof.

R¹ is preferably unsubstituted or substituted with one or two groupsselected from methyl, methoxy, CF₃ or halogen. Most preferably R¹ isunsubstituted.

R² is preferably hydrogen, methyl or (CH₂)_(q)C(O)OR⁶, for example R² is^(t)butyloxycarbonyl or hydrogen.

R⁴ is preferably hydrogen, methyl, methoxy, halogen, OCF₃ or CF₃. Inparticular, R⁴ is hydrogen.

R⁵ is preferably hydrogen, methyl, methoxy, halogen OCF₃ or CF₃. Inparticular R⁵ is hydrogen.

R⁶ is preferably hydrogen, C₁₋₄ alkyl or C₅₋₆ cycloalkyl. In particularR⁶ may be hydrogen or ^(t)butyl.

R⁷ and R^(7a) are preferably independently chosen from hydrogen,halogen, CF₃, methyl, methoxy and OCF₃. In particular both are hydrogen.

V is preferably an unsubstituted or substituted C₅₋₆ cycloalkyl orbenzene. It is to be noted that the group (CH₂)_(y) or, as the case maybe R³ is attached to any position of this ring, but the 3- and4-positions are preferred. Most particularly V is cyclohexane orbenzene.

m is preferably 0 or 2

q is preferably 0, 1 or 2

t is preferably 0 or 1

x+y is preferably 0, 1, 2, 3 or 4, in particular 0 or 3.

Thus there is a preferred subclass of compounds of formula Ia:

wherein R¹ is unsubstituted naphthyl or benzothienyl;

R² is hydrogen or C(O)OR⁶;

R⁶ is C₁₋₄ alkyl;

Q is —(CH₂)_(x)—C(R⁷)(R^(7a))—(CH₂)_(y)— or —(CH₂)_(x)—V—(CH₂)_(y)—;

V is cycloalkyl or benzene;

x is 0, 1 or 2;

y is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

The term “alkyl” refers to a monovalent alkane (hydrocarbon) derivedradical which may be straight, branched or cyclic. Examples of alkylgroups are methyl, ethyl, propyl, isopropyl, butyl and t-butyl. “Alkoxy”groups are to be construed analogously.

The term “C₃₋₈ cyclic ring” includes groups such as cyclopentyl,cyclohexyl and methylcyclohexyl.

The term “halogen” is intended to include fluorine, chlorine, bromineand iodine.

Salts encompassed within the term “pharmaceutically acceptable salts”refer to non-toxic salts of the compounds of this invention which aregenerally prepared by reacting the free base with a suitable organic orinorganic acid. Representative salts include the following:

Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,Borate, Camsylate, Carbonate, Citrate, Dihydrochloride, Edetate,Edisylate, Estolate, Esylate, Fumarate, Gluconate, Glutamate,Hydrobromide, Hydrochloride, Hydroxynaphthoate, Lactate, Lactobionate,Laurate, Malate, Maleate, Mandelate, Mesylate, Mucate, Napsylate,Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate(Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate,Tannate, Tartrate, Tosylate, and Valerate. A preferred salt isHydrochloride.

The compounds of the present invention may contain one or moreasymmetric carbon atoms and may exist in racemic and optically activeforms. All of these compounds are contemplated to be within the scope ofthe present invention. Therefore, where a compound is chiral, theseparate enantiomers, substantially free of the other, are includedwithin the scope of the invention; further included are all mixtures ofthe two enantiomers. Also included within the scope of the invention arepolymorphs and hydrates of the compounds of the instant invention.

Asymmetric centers may be present in the compounds of the instantinvention depending upon the nature of the various substituents on themolecule. Each such asymmetric center will independently produce twooptical isomers and it is intended that all of the possible opticalisomers and diastereomers in mixture and as pure or partially purifiedcompounds are included within the ambit of this invention.

A prefered chiral configuration of the compounds of formula I is:

The ability of the compounds of the present invention to act as ligandsfor CGRP makes them useful as pharmacological agents for humans andanimals, but particularly humans, for the treatment and prevention ofdisorders where CGRP may be involved. Such disorders include migraine,pain, cardiovascular disorders, inflammation, diabetes, Reynaud'ssyndrome, peripheral arterial insufficiency, subarachnoid and othercranial haemorrhages and as antitumour agents by controlling the flow ofblood to tumours. Of these conditions, the treatment of migraine isparticularly important.

The present invention therefore also provides a pharmaceuticalcomposition comprising a compound of the present invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each including timed release andsustained release formulations), pills, powders, granules, elixers,tinctures, suspensions, syrups and emulsions. Likewise, they may also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, all using forms well known to thoseof ordinary skill in the pharmaceutical arts.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

Intravenous dosages or oral dosages of the compounds of the presentinvention, when used for the indicated effects, will range between about0.001 to 5 mg/kg and 0.1 to 50 mg/kg, respectively. Advantageously,compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three or four times daily. Furthermore, preferred compounds for thepresent invention can be administered in intranasal form via topical useof suitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin that art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as “carrier” materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, zanthan gum andthe like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

The present invention also provides a compound of the present inventionor a pharmaceutically acceptable salt thereof for use in a method oftreatment of the human or animal body by surgery, therapy or diagnosis.

There is also provided the use of a compound of the present invention ora pharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of a condition with which CGRP isassociated such as migraine, pain, cardiovascular disorders,inflammation, diabetes, Reynaud's syndrome, peripheral arterialinsufficiency, subarachnoid and other cranial haemorrhages and tumoursby controlling blood flow.

There is further disclosed a method of treating or protecting a subjectsuffering from or prone to a condition associated with CGRP byadministering to that subject a therapeutically or prophylacticallyeffective amount of a compound of the present invention or apharmaceutically acceptable salt thereof.

The preparation of compounds of Formula I of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesdetailing the preparation of the compounds of Formula I are presented inthe following reaction schemes.

The phrase “standard peptide coupling reaction conditions” is usedrepeatedly here, and it means coupling a carboxylic acid with an amineusing an acid activating agent such as EDC, DCC, and BOP in a inertsolvent such as dichloromethane in the presence of a catalyst such asHOBT. The phrase “mixed urea formation” refers to conversion of twodifferent amines to form their mixed urea by using phosgene orequivalents such as CDI, DSC, or p-nitrophenyl chloroformate. Thereaction involves reacting one amine first with the phosgene orequivalents in the presence of a base such as NMM, TEA or DIEA in ainert solvent such as dichloromethane, THF and DMIF or mixtures thereof,followed by addition of the second amine and a base such as NMM, TEA orDIEA. The uses of protective groups for amines and carboxylic acids tofacilitate the desired reaction and minimize undesired reactions arewell documented. Conditions required to remove protecting groups whichmay be present can be found in Greene, T, and Wuts, P. G. M., ProtectiveGroups in Orgaitic Synthesis, John Wiley & Sons, Inc., New York, N.Y.1991. CBZ and BOC were used extensively and their removal conditions areknown to those skilled in the art. For example, removal of CBZ groupscan be achieved by a number of methods such as catalytic hydrogenationin the presence of a noble metal or its oxide such as palladium onactivated carbon in a protic solvent such as ethanol. In cases wherecatalytic hydrogenation is contraindicated by the presence of otherpotentially reactive functionality, removal of CBZ groups can also beachieved by treatment with a solution of hydrogen bromide in aceticacid, or by treatment with a mixture of TFA and dimethyl sulfide.Removal of BOC protecting groups is carried out in a solvent such asmethylene chloride, methanol or ethyl acetate, with a strong acid, suchas trifluoroacetic acid, hydrochloric acid or hydrogen chloride gas.

The protected amino acid derivatives required in the synthesis ofcompounds of Formula 1 are, in many cases, commercially available, wherethe protecting group (P¹) is, for example, methyl, allyl or benzylgroups. Other protected amino acid can be prepared by literature methods(Williams, R. M. Synthesis of Optically Active α-Amino Acids, PergamonPress: Oxford, 1989). Many of the piperidines of Formula 2 are eithercommercially available or known in the literature and others can beprepared following literature methods described for analogous compounds.Some of these methods are illustrated in the subsequent schemes.Purification procedures include crystallization, normal phase or reversephase chromatography.

The compounds of the present invention can be prepared readily accordingto the following Schemes or modifications thereof using readilyavailable starting materials, reagents and conventional synthesisprocedures. In these reactions, it is also possible to make use ofvariants which are themselves known to those of ordinary skill in thisart, but are not mentioned in greater detail. The definition for R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R^(7a) and Q is described above unless otherwisestated.

Intermediates of Formula 4A can be synthesized as described in Scheme 1.Mixed urea formation between the protected amino acid 1 and thepiperidine of Formula 2, is conveniently carried out under usual ureaformation reactions use phosgene or equivalents such as CDI, DSC, orp-nitrophenyl chloroformate. Removal of the P¹ protecting group can beachieved by saponification for most esters, or by catalytichydrogenolysis when P¹ is benzyl, or by palladium (0) based homogeneouscatalysis when P¹ is allyl. Intermediate 4A can be used as a commonintermediate with variation of the rest of the molecule of Formula I asshown in Scheme 2.

Intermediates of formula 4 (the first compound above) can be coupled tointermediates of formula 5 (the second compound above) under standardester or peptide coupling reaction conditions. Primary amine R³ may beprotected by a group such as BOC, Cbz, etc. which is subsequentlyremoved. Many of the selectively protected diamines or amino alcohols ofFormula 5 are either commercially available or known in the literatureand others can be prepared following literature methods described foranalogous compounds. Some of these methods are illustrated in subsequentschemes. The compound 4 is also generally protected with a protectinggroup as defined above.

Alternatively, compounds of Formula I can be prepared starting fromcompound 5. The protected amino acid derivatives 8 (the first compoundabove) are in many cases commercially available, where P3 is, forexample, BOC, Cbz, Fmoc, and the like. N-Protected amino acid 8 can becoupled to intermediates of formula 5, to afford compounds of Formula 9(the first product above) under standard ester or peptide couplingreaction conditions. The protecting group in compound 8 is selected withthe criteria that its removal can be achieved without removing P². Whenthe P² protecting group is removed to afford compound 10 (the secondproduct above), this compound can be further converted to compounds offormula I-A according to the procedures described in Scheme 1. Again R³is optionally protected.

The piperidinylbenzimidazolinone 2 without substitution is commerciallyavailable; derivatives with substituents on the benzene ring areprepared by the methods shown in Scheme 4 as described in J. Med. Chem.,30, 814-819 (1987) and U.S. Pat. No. 3,910,930, hereby incorporated byreference. P⁴ is a protecting group such as benzyl, methyl, BOC, Cbz,ethyloxycarbonyl and the like. Thus, condensation of the commerciallyavailable 4-aminopiperidine 11, where P⁴ is C(O)OEt, with a substitutedo-halo nitrobenzene 12 gives the nitro compound 13. Reduction of thenitro group to an amine can be accomplished by catalytic hydrogenationwith a catalyst such as Raney Ni, palladium on carbon or platinum oncarbon in a protic solvent such as ethanol. Ring closure can be effectedby phosgene or its equivalent such as DSC, CDI in the presence of abase. The protecting group P⁴ can be removed by alkaline hydrolysis inthe case of C(O)OEt or can be removed by the standard deprotectionconditions as described in Greene, T, and Wuts, P. G. M., ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc., New York, N.Y.1991.

In many cases, compounds of Formula 5 or its mono protected form withinthe scope of this invention are either commercially available or knownin the art. Mono Boc protected amine can be prepared by reacting excessdiamine with Boc₂O in methanol, where Boc protected amino alcohols canbe preprared by reacting the amino alcohol with BOc₂O.

Other compounds in the above schemes are commercially available or canbe made from commercially available compounds by standard methods.

Compounds of Formula 5 can be amino acids, which in some cases arecommercially available. Amino acids can be modified to give compounds asdefined by the scope of the instant application. For example, with thetwo amino groups properly protected, the carboxylic acid can beconverted into its next higher homologue, or to a derivative of thehomologous acid, such as amide or ester by an Arndt-Eistert reaction.The acid can also be converted amides with a variety of amines asdefined. The acid can be reduced to alcohol, which can be converted toether by alkylation or reduced with methods known to those skilled inthe art.

Optically pure cis-3-aminomethyl-1-BOC-aminomethyl cyclohexaneenantiomers are prepared (Scheme 5) starting from commercially availablem-cyanobenzoic acid. Reduction of the nitrile with Raney Ni/H₂ isfollowed by protection of the resulting 1° amino group. Reduction of thearomatic ring is then accomplished using PtO₂ as catalyst to givepredominantly the cis-cyclohexane carboxylic acid. A sequence ofcrystallizations using either (S) or (R)-a-methylbenzylamine to form thesalt, generates the homochiral cis acids as shown below. Enantiomericpurity is evaluated by derivatization of the acids with Trp-OMe andintegration of the methoxy methyl singlets in the ¹H NMR spectra. Theabsolute stereochemistries are determined by solving the x-ray structurefor the pure salt obtained from crystallization with the S-enantiomer ofa-methylbenzylamine and are as shown in Scheme 5 below. Borane reductionof the pure acids, followed by coversion of the resulting alcohols totheir mesylates and displacement with azide anion furnishes thecorresponding azidomethyl compounds. Reduction of the azide group (Pd/C,H₂) gives the desired amines, ready for incorporation into final targetcompounds.

The racemic cis and trans-3-aminomethyl-1-BOC-aminomethyl cyclohexaneisomers are also prepared (Scheme 6) and incorporated into targetcompounds. Commercially available bis-aminomethylcyclohexane (sold as amixture of cis and trans isomers) is resolved into the pure cis and puretrans isomers by conversion to the dihydrochloride salts andcrystallization from methanol/ethyl acetate. Mono-BOC protection isaccomplished by slow addition of BOC₂O to an excess of the diamines.

Trans-1-N-BOC-amino-4-aminomethylcyclohexanes are prepared from thecommercially available amino acid shown below (Scheme 10). Protection ofthe amine as its phthalimide, followed by Curtius rearrangement givesthe amino-protected isocyanate. Trapping of the isocyanate witht-butanol, is then followed by removal of the phthalimide protectinggroup using hydrazine to provide the target amine, which is incorporatedinto various analogs.

Mono-protected-1,3-bisaminomethylbenzene intermediates also lead topotent analogs. These are prepared (Scheme 11) starting fromcommercially available in-xylylenediamine. Slow addition of BOC₂O to anexcess of diamine furnishes the mono-protected amine, which is employedin the synthesis of target compounds.

Racemic cis-3-aminomethyl-1-BO C-aminomethylcyclopentane is prepared asshown in Scheme 12. Reduction of the commercially available anhydridegive cis-hydroxymethylcyclopentane. Conversion to the bis-mesylate,followed by displacement with azide results in the correspondingbis-azide. Reduction of the azide groups and mono-protection (asdescribed previously) provides the desired intermediate amine.

The compounds of the present invention have been tested in a cell assayfor activity as ligands for the human CGRP receptor. The methodology forthis is as described in Semark et al. Molecular Neuropharmacology (1992)2, 311-317. Likewise their functional activity can be determined bymethods in that paper. The specific Examples of the present inventionall inhibited [¹²⁵I]hCGRP in SK-N-MC cell membranes with a Ki of lessthan 10 μM.

The preferred compounds of the invention are any or all of thosespecifically set forth in the Examples below. These compounds are not,however, to be construed as forming the only genus that is considered asthe invention, and any combination of the compounds or their moietiesmay itself form a genus. The following examples further illustratedetails for the preparation of the compounds of the present invention.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. All temperatures are degreesCelsius unless noted otherwise.

A suspension of D-β-(3-benzothienyl)alanine methyl ester (2.45 mmol),disuccinimidyl carbonate (0.626 g, 1.0 equiv.) and DIEA (0.426 mL, 4equiv.) in dichloromethane (20 mL) was stirred at room temperature for30 minutes, during which time the reaction becomes clear.4-(2-Keto-1-benzimidazolinyl)piperidine (0.568 g) was added and themixture was permitted to stir overnight. The reaction mixture wasdiluted with dichloromethane, and washed in succession with 1N HCl,saturated NaHCO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The resulting crude product was purified by silica flashcolumn chromatography eluting with ethyl acetate to afford the methylester intermediate (1.09 g).

To a stirred solution of the methyl ester (1.09 g) from the previousstep in THF/AMeOH/H₂O (1:1:1) was added lithium hydroxide (384 mg) at 0°C. The reaction mixture was stirred for 4 h and was quenched by theaddition of hydrochloric acid (2 equiv.). The mixture was thenevaporated to remove the solvents, and partitioned between dilutehydrochloric acid and ethyl acetate. The organic extracts were washedwith brine, dried over magnesium sulfate and evaporated to give thedesired intermediate (1.1 g, crude).

Intermediate 2 was similarly prepared as Intermediate 1 usingD-β-(1-naphthyl)-Alanine methyl ester and4-(2-Keto-1-benzimidazolinyl)piperidine.

EXAMPLE 1

To a solution of Intermediate 1 (53 mg), HOBt (1 equiv.), andLys(Cbz)OBu^(t) (41 mg) in dichloromethane (2 mL) at 0° C., was addedEDC (32 mg, 1.5 equiv.) and the resulting solution was stirred for 4 h.The reaction mixture was then diluted with dichloromethane and washedwith dilute HCl, brine, saturated NaHCO₃ and dried over MgSO₄. Afterfiltration and evaporation, the residue was purified by silica elutingwith 2% methanol in ethyl acetate to give the Cbz intermediate (79 mg).

The intermediate prepared as described above (60 mg) was combined with10% Pd/C (10 mg) and concentrated HCl (1 equiv.) inethanol (5 mL). Thismixture was stirred under a H₂ balloon for 1 day and during which time 3batches 10% Pd/C (10 mg each) was added. The mixture filtered throughcelite. The filter cake was washed with an additional 10 mL of ethanoland the combined filtrates were concentrated to give the desired productas a hydrochloride salt (50 mg).

EXAMPLE 2

To a solution of Intermediate 1 (53 mg), HOBt (1 equiv.), andtrans-4-aminomethyl-1-(cyclohexylmethyll-carbamic acid tert-butyl ester(58 mg) in dichloromethane (2 mL) at 0° C., was added EDC (32 mg, 1.5equiv.) and the resulting solution was stirred for 4 h. The reactionmixture was then diluted with dichioromethane and washed with diluteHCl, brine, saturated NaHCO₃ and dried over MgSO₄. After filtration andevaporation, the residue was purified by silica eluting with 5% methanolin ethyl acetate to give the Boc intermediate (58 mg). Treatment of theintermediate with 4 N HCl in dioxane (1 mL) in ethyl acetate (2 mL) gavethe desired product (41 mg) after evaporation.

EXAMPLE 3

To a solution of Intermediate 2 (120 mg), HOBt (1 equiv.), and3-aminomethylbenzyl-carbamic acid tert-butyl ester (62 mg) indichloromethane (5 mL) at 0° C., was added EDC (60 mg, 1.5 equiv.) andthe resulting solution was stirred for 2 days during which time thereaction mixture was warmed to ambient temperature. The reaction mixturewas diluted with dichloromethane and washed with dilute HCl, brine,saturated NaHCO₃ and dried over MgSO₄. After filtration and evaporation,the residue was purified by silica eluting with 7% methanol in ethylacetate to give the Boc intermediate (110 mg). Treatment of theintermediate with 4 N HCl in dioxane (2 mL) in ethyl acetate (2 mL) gavethe desired product (90 mg) after evaporation.

EXAMPLE 4

To a solution of Intermediate 2 (100 mg, 0.218 mmol), HOBt (31 mg, 1.05equiv.), and [3(R)-aminomethyl-1(S)-cyclohexylmethyl]-carbamic acidtert-butyl ester (56 mg, 1.05 equiv.) in dichloromethane (8 mL) at 0°C., was added EDC (50 mg, 1.2 equiv.) and the resulting solution wasstirred for 2 days. The reaction mixture was then diluted withdichloromethane and washed with dilute HCl, brine, saturated NaHCO₃ anddried over MgSO₄. After filtration and evaporation, the residue waspurified by silica eluting with 7% methanol in ethyl acetate to give theBoc intermediate (100 mg). Treatment of the intermediate with 4 N HCl indioxane (1 mL) in ethyl acetate (2 mL) gave the desired product afterevaporation.

What is claimed is:
 1. A compound of formula I

wherein: R¹ is naphthyl or benzothienyl which is unsubstituted orsubstituted at up to three substitutable positions independently by C₁₋₆alkyl, halogen, C₁₋₆ alkoxy, CF₃, OCF₃, NO₂, CN, methylenedioxy orethylenedioxy; R² is hydrogen, C₁₋₈ alkyl, —(CH₂)_(t)-aryl wherein arylis selected from phenyl, biphenyl and naphthyl, —(CH₂)_(t)-heteroarylwherin heteroaryl is selected from tetrazolyl, oxadiazolyl,thiadiazolyl, triazolyl and pyrazinyl, —(CH₂)_(q)C(O)OR⁶, —(CH₂)_(q)OR⁶,—(CH₂)_(q)OC(O)R⁶, —(CH₂)_(q)C(O)R⁶, —(CH₂)_(q)C(O)(CH₂)_(t)aryl,—(CH₂)_(q)N(R⁶)C(O)R⁶, —(CH₂)_(q)C(O)N(R⁶)₂, —(CH₂)_(q)N(R⁶)SO₂R⁶,—(CH₂)_(q)N(R⁶)C(O)N(R⁶)₂, —(CH₂)_(q)OC(O)N(R⁶)₂,—(CH₂)_(q)N(R⁶)C(O)OR⁶, —(CH₂)_(q)N(R⁶)SO₂N(R⁶)₂ and—(CH₂)_(q)S(O)_(m)R⁶; R³ is NH₂; R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, OCF₃ or CF₃; R⁵ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,halogen, OCF₃ or CF₃; R⁶ is hydrogen, C₁₋₈ alkyl or C₃₋₇ cycloalkyl, andwhen two R⁶ groups are present and both represent C₁₋₈ alkyl they mayoptionally together with the atom to which they are both attached form aC₃₋₈ ring; Q is —(CH₂)_(x)—C(R⁷)(R^(7a))—(CH₂)_(y)— or—(CH₂)_(x)—V—(CH₂)_(y)—; R⁷ and R^(7a) are independently chosen fromhydrogen, CF₃, halogen, C₁₋₆ alkyl and C₁₋₆ alkoxy; V is a C₃₋₈non-aromatic cyclic or bicyclic ring or an aromatic ring which isbenzene or naphthalene, said ring being unsubstituted or substituted atup to three substitutable positions independently by C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, OCF₃, CF₃, CN, NO₂, methylenedioxy or ethylenedioxy; mis 0, 1 or 2; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; x and y areindependently 0, 1, 2, 3 or 4; or a pharmaceutically acceptable saltthereof.
 2. A compound of formula Ia:

wherein R¹ is unsubstituted naphthyl or benzothienyl; R² is hydrogen orC(O)OR⁶; R⁶ is C₁₋₄ alkyl; Q is —(CH₂)_(x)—C(R⁷)(R^(7a))—(CH₂)_(y)— or—(CH₂)_(x)—V—(CH₂)_(y)—; V is cycloalkyl or benzene; X is 0, 1 or 2; yis 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
 3. Acompound which is:

in free base form or as a pharmaceutically acceptable salt.
 4. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier.
 5. A method of treating adisease or condition selected from the group consisting of: (a)migraine, (b) pain, (c) cardiovascular disorder, (d) inflammation, (e)diabetes, (f) Reynaud's syndrome, (g) peripheral arterial insufficiency,(h) cranial hemorrhage and (i) tumor, comprising administering to saidpatient a therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.